Unhealthy alcohol use is common among HIV-infected persons and it adversely affects health. Injection drug use accounts for 1 in 5 cases of HIV infection, thus opioid dependence is also common. More than one-third of those with HIV infection and other drug use drink too much alcohol. Research has focused on either alcohol or drug use in HIV-infected individuals, but much less is known about alcohol's health effects in HIV- infected people affected by multiple substances of abuse. This proposal is a component of the Uganda Russia Boston Alcohol Network for Alcohol Research Collaboration on HIV/AIDS (URBAN ARCH) Consortium, whose goal is to examine the consequences of alcohol on HIV disease and to mitigate its harms. The objective of this proposal is to accurately characterize alcohol use and consequences in people with HIV infection affected by multiple substances, and to implement observational and intervention studies to understand and reduce alcohol's harm. The proposal has 3 specific aims: 1) To expand and continue an existing cohort to establish the longitudinal Boston ARCH Cohort of 250 HIV-infected men and women affected by multiple substances-a spectrum of alcohol use, and all with substance dependence or Injection drug use. 2) To treat both heavy drinking and opioid dependence with one medication. The Treating With Opioids For Ethanol Risks (TWOFER) trial will assess if high-dose buprenorphine (32mg) reduces heavy drinking compared to standard-dose (16mg) at 3 months in a randomized double-blind placebo-controlled trial among 100 HIV-infected adult Cohort participants with opioid dependence and heavy drinking. If efficacious, buprenorphine, a treatment for opioid dependence, could be easily disseminated as a treatment for unhealthy alcohol use in people with HIV infection and opioid dependence as only dose adjustment is required. 3) Because alcohol, opioid use, HIV infection and antiretroviral therapy may affect bone health and increase fracture risk, analysis of cohort data will determine the independent effect of alcohol consumption on changes in bone mineral density and microarchitecture (by high-resolution computed tomography) prospectively in all Cohort participants over 12-42 months. The Cohort will yield data on alcohol effects on bone, important information for defining risky drinking amounts in people with HIV infection and for advising them on alcohol-related risks. Thus, these studies will provide substantial new knowledge for mitigating alcohol consequences among HIV-infected adults affected by multiple substances. PUBLIC HEALTH RELEVANCE: HIV disease can be treated effectively, but drinking too much interferes with treatment and causes bone loss, especially among those who abuse other drugs. This research will study people with HIV infection to discover what amounts of alcohol increase risk of fractures, and to see whether a medication used for drug addiction can also reduce heavy drinking. Findings will be useful for advising people with HIV infection about drinking limits to prevent fractures and may identify a new treatment to reduce drinking and improve health.